Compounds useful for treating aids

ABSTRACT

A compound having the following formula or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where:
         R independently represents a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, a —NR 1 R 2  group, a (C 1 -C 3 )fluoroalkoxy group, a —NO 2  group, a phenoxy group, or a (C 1 -C 4 )alkoxy group,   R 1  and R 2  are independently a hydrogen atom or a (C 1 -C 3 )alkyl group,   R′ is a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, or a (C 1 -C 4 )alkoxy group,   R″ is a hydrogen atom or a (C 1 -C 4 )alkyl group,   n is 1, 2, or 3, and   n′ is 1 or 2.

This is a continuation of application Ser. No. 13/377,760 filed Jul. 2,2012, which is a National Stage Application of PCT/IB2010/052651 filedJun. 14, 2010, and claims the benefit of U.S. Provisional ApplicationNos. 61/186,544 and 61/186,552 and European Application Nos. 09162630.9and 09305540.8, all of which were filed on Jun. 12, 2009. The entiredisclosures of the prior applications are hereby incorporated byreference herein in their entirety.

The invention relates to novel compounds for the preparation ofcompositions useful for the treatment of diseases resulting from changesin splicing processes.

Certain indole derivative compounds such as ellipticine derivatives andaza-ellipticine derivatives are already known as intercalating moleculesfor correcting dysfunctions in gene expression, notably in DNAreplication. They have been more specifically described for treatingdiseases such as cancer, leukemia or AIDS (see in particular patents FR2 627 493, FR 2 645 861, FR 2 436 786).

Concerning current treatments for AIDS, the various approaches aimed atreducing viral load in patients infected by HIV utilize moleculesintended to inhibit the enzymatic activity of viral reversetranscriptase or of the protease involved in virus protein maturation.Regarding reverse transcriptase inhibitors, these can be nucleosidic(NRTIs), non-nucleosidic (NNRTIs) or nucleotidic in nature. The purposeof using these compounds is to prevent a DNA copy of the retroviralgenome from being produced and, consequently, from being integrated intothe genome of the host cell. Protease inhibitors (PIs) interfere withthe proper maturation of viral proteins and cause the production ofincomplete particles with altered infectious capacities. There isanother type of anti-retroviral compound used for its ability to preventviruses from entering the cell. These entry inhibitors can be eitherpeptides that interfere with the fusion of viral glycoproteins gp41 orgp120 with the membrane of CD4 cells or molecules that target HIVcellular co-receptors CCR5 and CXCR4. The absence of cellular proteinsresembling HIV integrase has also been exploited to develop novelanti-HIV molecules that inhibit this enzymatic activity. Although anumber of integrase inhibitors are in the clinical trial phase, nomolecule is yet available on the market.

The intracellular splicing process consists of eliminating introns inpre-messenger RNAs to produce mature messenger RNAs that can be used bythe translation mechanism of the cell (SHARP, Cell, vol. 77, p. 805-815,1994). In the case of alternative splicing, the same precursor can bethe source of messenger RNAs coding for proteins with distinct functions(BLACK, Annu. Rev. Biochem. vol. 72, p. 291-336, 2003). The preciseselection of 5′ and 3′ splicing sites is thus a mechanism that generatesdiversity and that can lead to the regulation of gene expressionaccording to the type of tissue or during the development of anorganism. The factors involved in this selection include a family ofproteins called SR, characterized by the presence of one or two RNArecognition motifs (RRM) and a domain rich in arginine and serineresidues called an RS domain (MANLEY & TACKE, Genes Dev., vol. 10, p.1569-1579, 1996). By binding to short exon or intron sequences of thepre-mRNA, called ESE (exonic splicing enhancer) or ISE (intronicsplicing enhancer), SR proteins are able to activate, in adose-dependant manner, sub-optimal splicing sites and to enable theinclusion of exons (GRAVELEY, RNA, vol. 6, p. 1197-1211, 2000). Theactivity of an SR protein in alternative splicing is specific insofar asthe inactivation of the corresponding gene is lethal (WANG et al., Mol.Cell, vol. 7, p. 331-342, 2001).

Sequencing of the human genome and analysis of EST (expressed sequencetag) banks has revealed that 65% of genes are expressed in the form ofalternatively spliced variants (EWING & GREEN, Nat. Genet., vol. 25, p.232-234, 2000; JOHNSON et al., Science, vol. 302, p. 2141-2144, 2003).This mechanism is thus a favored target of modifications that can affectthe factors involved in regulating splicing and of mutations that affectthe sequences necessary for this regulation. At present, it is estimatedthat roughly 50% of the point mutations responsible for genetic diseasesinduce aberrant splicing. These mutations can interfere with splicing byinactivating or creating splicing sites, but also by modifying orgenerating regulating elements such as splicing enhancers or splicingsilencers in a particular gene (CARTEGNI et al., Nat. Rev. Genet., vol.3, p. 285-298, 2002; TAZI et al., TIBS, vol. 40, p. 469-478, 2005).

The strategies currently developed to correct these splicing defectsrest on the use of various types of molecules (TAZI et al., cited above,2005).

One strategy aimed at developing novel molecules to correct or eliminateabnormal splicing, for example, rests on the overexpression of proteinsthat interfere with this type of splicing (NISSIM-RAFINIA et al., Hum.Mol. Genet., vol. 9, p. 1771-1778, 2000; HOFINANN et al., Proc. Natl.Acad. Sci. USA, vol. 97, p. 9618-9623, 2000).

Other strategies rest on the use of antisense oligonucleotides (SAZANIet al., Nat. Biotechnol., vol. 20, p. 1228-1233, 2002; SAZANI & KOLE,Prog. Mol. Subcell. Biol., vol. 31, p. 217-239, 2003) or of PNA(CARTEGNI et al., Nat. Struct. Biol., vol. 10, p. 120-125, 2003)enabling, respectively, the inhibition or activation of a splicingevent.

Yet another strategy rests on the identification of compounds thatinfluence the splicing efficiency of the pre-mRNA of interest (ANDREASSIet al., Hum. Mol. Genet., vol. 10, p. 2841-2849, 2001).

Lastly, a strategy based on the use of trans-splicing to replace mutantexons has been described (LIU et al., Nat. Biotechnol., vol. 20, p.47-52, 2002).

One of the disadvantages of the developed strategies cited above tocorrect or eliminate abnormal splicing is their production cost. Indeed,the cost of producing antisense oligonucleotides that must be modifiedto improve their stability, and that of PNA molecules, is high.

Another disadvantage of the developed strategies cited above is thatthey require the use of expression vectors, such as, for example, forthe strategy based on the use of trans-splicing.

International application WO05023255, under French priority ofapplications FRO310460 and FR0400973, filed by the Applicant, disclosedthe use of indole derivatives to treat diseases related to thepre-messenger RNA splicing process in the cell.

Thus it was recently shown that certain indole derivatives proveparticularly effective in treating metastatic cancer and in treatingAIDS (BAKKOUR et al., PLoS Pathogens, vol. 3, p. 1530-1539, 2007).

However, the compounds described have a flat structure with four ringsthat have the disadvantage of intercalating between DNA bases and canthus lead to cellular toxicity.

In order to minimize the risk that these indole derivatives intercalatebetween DNA bases, the inventors developed novel compounds that areparticularly effective in treating diseases related to the splicingprocess, but which, in a surprising manner, have a cellular toxicitythat is clearly less than the indole derivatives of the prior art. Inaddition, these compounds are able to selectively inhibit certainsplicing events.

According to a first aspect, a subject-matter of the present inventionrelates to a compound of formula (I)

-   -   wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group and a (C₁-C₃)alkylgroup, said alkyl being optionally mono-substituted by a hydroxyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group,a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

T is N or C,

U is N or C,

and wherein at most four of the groups V, T, U, Z, Y, X and W are N,

and at least one of the groups T, U, Y, X and W is N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, Tis C, U is C and W is C, for use as an agent for preventing, inhibitingor treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is C,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is C and W is N, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is C, X is N, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and in ortho of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, Xis N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and is in ortho of the bond linked to NR″, Y is N, X is N, T is C,U is C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is N and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

The compounds of the invention may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of compounds offormula (I) include hydrobromide, tartrate, citrate, trifluoroacetate,ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate,formate, acetate and fumarate.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

In the context of the present invention, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃        normal, secondary or tertiary saturated hydrocarbon. Examples        are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,    -   “(C₁-C₃)alkoxy” as used herein respectively refers to        O—(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.        Examples are, but are not limited to, methoxy, ethoxy,        1-propoxy, 2-propoxy,    -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively        to alkyl group and alkoxy group as above-defined, said groups        being substituted by at least one fluorine atom. Examples are        perfluoroalkyl groups, such as trifluoromethyl or        perfluoropropyl, and    -   “patient” may extend to humans or mammals, such as cats or dogs.

According to one preferred aspect, the present invention relates to acompound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in para of Z, Y is N, X is C, T is C, U is C and W is C, for use asan agent for preventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

Another object of the present invention relates to a compound of thefollowing formula (P):

wherein:

X1, X2 and X3 independently represent a nitrogen atom, or a CR8 group,at least one of X1 and X2 being a nitrogen atom;

R8 represents a hydrogen atom or a halogen atom, a hydroxyl, alkyl,trifluoroalkyl, ester, ether, such as a methoxy or trifluoromethoxygroup, or benzyl, optionally substituted, a nitro or a cyano group,preferably R8 represents a hydrogen atom,

when a ring A, defined below, is in position a, X4 represents a nitrogenatom or a CR8 group, and when a ring A is in position b, X4 represents acarbon atom part of the ring A,

R1, R2, R3 and R5 independently represent a hydrogen or a halogen atom,an alkyl, a trifluoroalkylgroup, ether, such as a methoxy ortrifluoromethoxy group, or benzyl, optionally substituted, a nitro or acyano group.

when the ring A is at position b, R4 represents a hydrogen atom, ahalogen atom or an alkyl, a trifluoroalkyl, ester, ether group, such asa methoxy or trifluoromethoxy group, or benzyl, optionally substituted,and when the ring A is at position a, R4 is a carbon atom part of thering A,

R10 represents a carbon atom part of ring A,

R6 represents a hydrogen atom or an alkyl group,

A represents a ring at position a or b of formula I, said ring Acorresponding to:

wherein:

R7 represents a hydrogen, or halogen atom or an alkyl, hydroxyl or aminegroup which can be linear or branched and/or unsaturated and optionallysubstituted,

pharmaceutically acceptable salts of said compounds, isomers thereofand/or mixtures of the same,

with the exception of the following compound:

“Halogen atom” means the group comprising F, Cl, Br and I, preferablysaid halogen atom is a chlorine atom.

“Unsaturated” means that the group comprises at least one double bond.

All the compounds disclosed in the examples are in the scope of thepresent invention.

Preferably, X1 represents a CR8 group when X2 represents a nitrogengroup, and

X2 represents a CR8 group when X1 represents a nitrogen group.

Preferably, at least one of X3 and X4 is a nitrogen atom when the cycleA is in position a.

Preferably X3 and X4 are different, and even more preferably X3represents a CR8 group when X2 represents a nitrogen group or a and X4represents a CR8 group when X1 represents a nitrogen group.

Preferably, R1 represents a hydrogen atom or a methoxy group.

Preferably, R2, R3, R4 and R5 independently represent a hydrogen atom ora halogen atom or an alkyl, or benzyl, optionally substituted.

Preferably, R4 represents a hydrogen atom.

Preferably, R2 represents a hydrogen atom or a C1 to C4 alkyl group,preferably a methyl.

Preferably, R3, R5 and R6 independently represent a hydrogen atom.

Preferably, R7 represents a hydrogen, or halogen atom, more preferably ahydrogen or a chlorine atom.

Preferably, the ring A is attached at position a or b of the compound offormula I via the carbons numbered 1 and 2 in ring A.

Preferably, when the ring A is at position a, R4 is the carbon atomnumbered 2 of the ring A, more preferably R4 is the carbon atom numbered2 of the ring A and R10 is the carbon numbered 1.

Preferably, when a ring A is in position b, X4 is the carbon atomnumbered 1 of the ring A, more preferably, X4 is the carbon atomnumbered 1 of the ring A and R10 is the carbon numbered 2.

Preferably, the compound as described above does not include thefollowing compounds:

5,8-Dimethyl-6-(pyridin-2-ylamino)-2H-isoquinolin-1-one

5,8-diméthyl-6-(3 methoxy-pyridin-2-ylamino)-isoquinolin-1-one

5,8-Dimethyl-6-(pyridin-2-ylamino)-2H-isoquinolin-1-one

Advantageously, the compound of formula I is chosen among the groupcomprising:

Pyridin-4-yl-quinolin-3-yl-amine; compound (121) of table I

(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine; compound (6) oftable I

(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine; compound (10) of table I;and

Isoquinolin-5-yl-(3-methoxy-pyridin-2-yl)-amine

According to a particular embodiment, an additional subject-matter ofthe present invention is a compound of formula (Ia)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a —NR₁R₂group,

R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxygroup, a —NO₂ group, a phenoxy group and a (C₁-C₄)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is preferably 1 or 2,

n′ is as defined above and is preferably 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂ group, a —COOR₁group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Id)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a (C₁-C₃)alkoxygroup,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (If)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ig)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ih)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ii)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Il)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Im)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a halogen atom or a groupchosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl group, saidalkyl being optionally mono-substituted by a hydroxyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ip)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iq)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoroalkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, aN-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a morpholino group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ir)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, amorpholino group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iee)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 2,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Among the previous defined families of compounds of formulae (Ia) to(Iee), some are more particularly preferred for their use as an agentfor preventing, inhibiting or treating AIDS. These preferred compoundsparticularly belong to formulae (Ia), (Ib), (Ic), (Ie) and (Io), asdefined above or one of its pharmaceutically acceptable salts.

Accordingly the present invention further relates to a compound offormula (Ia), (Ib), (Ic), (Ie) and (Io), as defined above, for use as anagent for preventing, inhibiting or treating AIDS.

Thus, according to a more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, ahydroxyl group, a —CN group, a-COOH group and a (C₁-C₃)alkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom, a halogen atom, a —NO₂ group or a (C₁-C₃)alkylgroup,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ia′),

wherein,

R independently represent a hydrogen atom, a —CN group, a (C₁-C₃)alkylgroup, a (C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl group,

R′ is as defined in formula (Ia) and is preferably a halogen, a(C₁-C₃)alkyl group or a NO₂ group,

R″ is a hydrogen atom,

n is 1 or 2

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom, a groupchosen among a (C₁-C₄)alkyl group, a —NR₁R₂ group, a (C₁-C₃)alkoxy groupand a (C₁-C₃)fluoroalkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above,

n′ is as defined above,

R′ is a hydrogen atom, halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ib′),

wherein:

R independently represent a hydrogen atom, a halogen atom, a groupchosen among a (C₁-C₃)alkoxy group, a (C₁-C₃)fluoroalkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ group and a(C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Io)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group and a —NO₂ group,

R″ is as defined above and more preferably is a hydrogen atom,

n is 1, 2 or 3,

n′ is as defined above,

R′ is a hydrogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

In a particular embodiment, the present invention relates to a compoundof formula (Ia), (Ic) or (Io) as defined above or one of itspharmaceutically acceptable salts, for use as an agent for preventing,inhibiting or treating AIDS.

According to a preferred embodiment of the present invention, thecompound for use as an agent for preventing, inhibiting or treatingAIDS, is chosen from:

-   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine-   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid-   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine-   (4) Pyridin-2-yl-quinolin-2-yl-amine-   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid-   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine-   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile-   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine-   (9) Pyridin-2-yl-quinolin-3-yl-amine-   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine-   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine-   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine-   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine-   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid-   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine-   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine-   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine-   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine-   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine-   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile-   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile-   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine-   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine-   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine-   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile-   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine-   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine-   (33) 2-(quinolin-2-ylamino)isonicotinonitrile-   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine-   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine-   (37) 8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine-   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine-   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile-   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid-   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride-   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride-   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine-   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine-   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine-   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile-   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine-   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine-   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine-   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (59) methyl 6-(quinolin-2-ylamino)nicotinate-   (60) methyl 6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate-   (61) methyl 6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate-   (62) methyl 2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate-   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine-   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine-   (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine-   (67) methyl 6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate-   (68) 8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol-   (70) 8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine-   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine-   (74) 3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine-   (76) N-(4-methoxyphenyl)quinolin-2-amine-   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine-   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine-   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine-   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine-   (85) N-(4-nitrophenyl)quinolin-2-amine-   (86) N-(3-fluorophenyl)quinolin-2-amine-   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine-   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride-   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (91)    3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine-   (94)    8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium    chloride-   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine-   (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium    chloride-   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine-   (102) N-(4-phenoxyphenyl)quinolin-2-amine-   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (104)    8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine-   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine-   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine-   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine-   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine-   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine-   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine-   (113) N-(pyrazin-2-yl)quinolin-2-amine-   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine-   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine-   (118) N-(pyridin-3-yl)quinolin-3-amine-   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine-   (120) N-(pyridin-4-yl)quinolin-2-amine-   (121) N-(pyridin-4-yl)quinolin-3-amine-   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine-   (123) N-(4-methoxyphenyl)quinolin-3-amine-   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (128) N-(pyrimidin-2-yl)quinolin-2-amine-   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine-   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine-   (131) N-(pyrazin-2-yl)quinolin-6-amine-   (132) N-(pyrazin-2-yl)quinolin-3-amine-   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine-   (134) N-(naphthalen-2-yl)pyridin-2-amine-   (135) N-(pyridin-2-yl)quinoxalin-2-amine-   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine-   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile-   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine-   (139) N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine-   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine-   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine-   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine-   (143)    4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine-   (144)    4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine-   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine-   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine-   (147)    4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine-   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine-   (149)    5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine-   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine-   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine-   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine-   (153) 6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine-   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine-   (156)    4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine-   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine-   (158)    N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine-   (159) N-(3-aminopyridin-2-yl)quinolin-3-amine-   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine-   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine-   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine-   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine-   (164) [2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol-   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine-   (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine-   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine-   (168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine-   and their pharmaceutically acceptable salts.

Among said compounds, compounds (1), (6), (33), (34), (35), (36), (37),(38), (42), (43), (44), (45), (46), (48), (50), (64), (68), (69), (70),(71), (72), (73), (74), (75), (77), (78), (79), (80), (81), (82), (86),(87), (88), (90), (92), (96), (104), (106), (109), (112), (136), (139),(140) and (141) are of particular interest.

The present invention therefore extends to compounds (1), (6), (33),(34), (35), (36), (37), (38), (42), (43), (44), (45), (46), (48), (50),(64), (68), (69), (70), (71), (72), (73), (74), (75), (77), (78), (79),(80), (81), (82), (86), (87), (88), (90), (92), (96), (104), (106),(109), (112), (136), (139), (140) and (141) or one of itspharmaceutically acceptable salts for use as an agent for preventing,inhibiting or treating AIDS.

Some of said preceding compounds are new and form part of the presentinvention: (1), (6), (33), (34), (35), (36), (37), (38), (42), (43),(44), (46), (48), (50), (64), (68), (69), (70), (71), (72), (73), (74),(75), (77), (78), (79), (80), (81), (82), (86), (87), (88), (90), (92),(96), (104), (106), (109), (112), (136), (139), (140), (141) and theirpharmaceutically acceptable salts, such as hydrobromide, tartrate,citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,maleate, mesylate, formate, acetate and fumarate.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) and (Tee) cancomprise one or more asymmetric carbon atoms. They can thus exist in theform of enantiomers or of diastereoisomers. These enantiomers,diastereoisomers and their mixtures, including the racemic mixtures, areencompassed within the scope of the present invention.

Among the compounds of formula (I), some of them are new and form partof the invention, as well as their pharmaceutically acceptable salts,such as hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate.

According to a particular embodiment, the present invention encompassescompounds of formula (Ig) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

and when n and n′ are 1 and R is a hydrogen atom then R′ is not a —COOHgroup,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (If) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ih) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Il) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Im) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that when n and n′ are 1 and R is a hydrogen atom, R′is not a chlorine atom,

or anyone of its pharmaceutically acceptable salt.

For a sake of simplification, the following compounds and theircorresponding definitions are called “new compounds”.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ia), as such, wherein:

R″ and n are as defined in formula (Ia),

n′ is 1,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R′ is a hydrogen atom or a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,

and wherein:

with the proviso that

when R and R′ are not simultaneously a hydrogen atom,

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

when R′ is a hydrogen atom, R is not a bromine atom or a chlorine atom,

when R is a hydrogen atom, R′ is not a methyl or ethyl group, a —COOHgroup, a COOC₂H₅ group or a bromine atom, said bromine atom being inortho position of the bond linked to NR″,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia), as such,wherein,

R independently represent a hydrogen atom, a (C₁-C₃)fluoroalkyl group, ahalogen atom, a —CN group or a (C₁-C₃) alkyl group,

R″ is as defined in formula (Ia),

R′ is a hydrogen atom, a halogen atom or a —NO₂ group,

n′ is 1,

n is 1,

with the proviso that

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

R is not a bromine atom or a chlorine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore preferably focuses on compounds of formula (Ia′), as such,

wherein,

R independently represent a hydrogen atom, a (C₁-C₃) alkyl group, a(C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl group,

R″ is as defined in formula (Ia),

n is 1 or 2, and preferably 1,

or one of its pharmaceutically acceptable salt.

The present invention further relates to a compound of formula (Ib) asdefined above, as such

wherein:

R′ and R″ are as defined in formula (Ib),

n is 1, and

R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,

-   -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib) wherein:

-   -   R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,    -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₄)alkyl group,    -   R″ is as defined in the formula (Ib),

n′ is 1 or 2 and is preferably 1,

n is 1 or 2 and is preferably 1,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (IW)

wherein:

R, R″ and n are as defined in formula (Ib),

-   -   R′ is as defined in formula (Ib),

with the proviso that R′ is different from a methyl group in position 4on the quinoline,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib″)

wherein:

-   -   R, R″ and n are as defined in formula (Ib),

with the proviso that when n is 1, R is not a hydrogen atom, a methylgroup in para of the bond linked to NR″, a ethoxy group in para of thebond linked to NR″, nor a fluorine atom in para of the bond linked toNR″,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ic), as such, wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

R is not a bromine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic), as such,wherein,

R is a hydrogen atom or a —NO₂ group,

n is 1,

R′, R″ and n′ are as defined in formula (Ic), and

R′ is preferably a (C₁-C₃)alkyl group or a hydrogen atom,

or one of its pharmaceutically acceptable salt.

The present invention further relates to a compound of formula (Ie) asdefined above, as such

wherein:

R, R′, R″ n and n′ are as defined in formula (I),

with the proviso that

when R is a hydrogen atom, R′ is not a bromine atom,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Io), as such, wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

when R is a hydrogen atom and n′ is 1, R′ is not a hydroxyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Io′), as such,wherein

wherein:

n is 1, 2 or 3,

n′ is 1 or 2,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, and is preferablya —NO₂ group, a hydrogen atom or a halogen atom,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, a (C₁-C₃)fluroralkylgroup, and preferably is a hydrogen atom or a (C₁-C₃)fluoroalkyl group,

R₁ and R₂ are as defined in formula (Io),

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

Among said compounds as such, compounds (1), (2), (5)-(8), (10)-(16),(18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130),(132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceuticallyacceptable salts are of particular interest.

The present invention therefore extends to compounds (1), (2), (5)-(8),(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121),(124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and theirpharmaceutically acceptable salts, as such.

More preferably, compounds (8), (75), (77)-(84), (86)-(104),(109)-(117), (155)-(158) and their pharmaceutically acceptable salts areof particular interest.

The present invention therefore extends more preferably to compounds(8), (75), (77)-(84), (86)-(104), (109)-(117), (155)-(158) and theirpharmaceutically acceptable salts, such as hydrobromide, tartrate,citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,maleate, mesylate, formate, acetate and fumarate.

Still more preferably, the present invention extends to compounds (75),(77), (78), (79), (80), (81), (82), (86), (87), (88), (90), (92), (96),(104), (109), (112), and their pharmaceutically acceptable salts, suchas hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate.

The new compounds of the present invention, i.e. compounds of formulae(Ia), (Ic), (Io), (Ib), (Ib′), (Ib″) and (Ie) and the specific compoundsas listed above, are not only useful as agent for inhibiting, preventingor treating AIDS but can also be useful for inhibiting, preventing ortreating premature aging and for inhibiting, preventing or treatingcancer, and more particularly colorectal cancer, pancreatic cancer, lungcancer including non-small cell lung cancer, breast cancer, bladdercancer, gall bladder cancer, liver cancer, thyroid cancer, melanoma,uterine/cervical cancer, oesophageal cancer, kidney cancer, ovariancancer, prostate cancer, head and neck cancer and stomach cancer, etc.

According to an aspect of the invention said compounds may be useful toinhibit, prevent and/or treat diseases with premature aging and that arelikely related to an aberrant splicing of the nuclear lamin A gene.Among all, said disease may include Hutchinson Guilford ProgeriaSyndrome (HGPS), progeria, premature aging associated with HIVinfection, muscular dystrophy, Charcot-Marie-Tooth disorder, Wernersyndrome, but also atherosclerosis, insulin resistant type II diabetes,cataracts, osteoporosis and aging of the skin such as restrictivedermopathy.

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below represent a general methoduseful for preparing the compounds of the present invention and are notmeant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 below.

As appears in said scheme two routes are available for recovering acompound of formula (I) according to the present invention.

The synthesis is based on a coupling reaction alternatively startingfrom a halogeno-bicycle of formula (III), wherein X, Y, W, T, U, n′, R′and R″ are as defined above and X′ is a chlorine atom or a bromine atomor from a chloro-monocycle of formula (V), wherein Z, V, n and R are asdefined above and X′ is a chlorine atom or a bromine atom.

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a molar ratio ranging from 1 to 1.5 with respect to thecompound of formula (III) in presence of an inorganic base, such asCs₂CO₃ or K₂CO₃ in a molar ratio ranging from 1 and 2, in the presenceof a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos(2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in an amountranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (III), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % and 10 mol %relative to the total amount of compound of formula (III). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

According to route (B) the compound of formula (V) is placed in a proticsolvent such as tert-butanol. The compound of formula (VI) is then addedin a molar ratio ranging from 1 to 1.5 with respect to the compound offormula (V) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃ ina molar ratio ranging from 1 to 2, in the presence of a diphosphine,such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) orX-Phos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in anamount ranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (V), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % to 10 mol %relative to the total amount of compound of formula (V). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

The starting compounds of formula (III), (IV), (V) and (VI) arecommercially available or can be prepared according to methods known tothe person skilled in the art.

The chemical structures and spectroscopic data of some compounds offormula (I) of the invention are illustrated respectively in thefollowing Table I and Table II.

TABLE I (I)

Formula (Ia) 1

2

3

4

5

6

7

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

150

151

152

153

154

Formula (Ib) 8

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

155

156

157

158

Formula (Ic) 9

10

11

12

13

14

105

106

159

Formula (Id) 15

16

107

108

Formula (Ie) 109

110

111

112

113

114

115

116

117

Formula (If) 118

Formula (Ig) 119

120

Formula (Ih) 121

Formula (Ii) 122

123

Formula (Ij) 124

125

126

127

Formula (Ik) 128

129

130

Formula (Il) 131

Formula (Im) 132

Formula (Io) 135

136

137

138

139

140

141

160

161

162

163

164

165

Formula (Ip) 142

Formula (Iq) 143

144

166

167

Formula (Ir) 145

146

147

168

Formula (Iee) 148

149

TABLE II Ex Characterizations 1 MS (ESI) [M + H]⁺ = 256 2 ¹H NMR (300MHz, D₂O) δ 8.31 (d, J = 5.1, 1H), 8.21 (d, J = 9.3, 1H), 7.60 (d, J =7.5, 3H), 7.34 (dd, J = 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J = 9.1,1H) MS (ESI) [M + H]⁺ = 266 5 MS (ESI) [M + H]⁺ = 300 6 ¹H NMR (300 MHz,DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 8.8, 2H), 7.78 (dd, J= 7.7, 13.7, 2H), 7.46 (d, J = 8.9, 1H), 7.31 (t, J = 7.8, 1H), 6.86 (d,J = 4.3, 1H), 2.37 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61,148.37, 147.32, 142.65, 137.52, 129.68, 129.47, 126.82, 125.06, 123.26,118.36, 115.10, 113.31, 21.24. MS (ESI) [M + H]⁺ = 270 7 ¹H NMR (300MHz, DMSO) δ 10.71 (s, 1H), 8.71 (d, J = 1.4, 1H), 8.62 (d, J = 8.9,1H), 8.24 (d, J = 8.9, 1H), 8.17 (dd, J = 1.9, 8.9, 1H), 7.89-7.74 (m,2H), 7.66 (dd, J = 7.9, 14.2, 2H), 7.42 (t, J = 7.3, 1H). ¹³C NMR (75MHz, DMSO) δ 156.09, 152.40, 152.11, 146.24, 141.07, 137.83, 129.87,127.67, 126.78, 124.50, 124.21, 118.04, 114.49, 111.67, 100.12. MS (ESI)[M + H]⁺ = 247 8 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9, 1H), 7.79(d, J = 8.4, 1H), 7.65 (t, J = 7.7, 3H), 7.59 (dd, J = 7.1, 8.3, 1H),7.31 (t, J = 7.0, 1H), 7.20 (d, J = 8.5, 2H), 6.88 (d, J = 8.9, 1H),6.80 (s, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 153.88, 147.62, 144.35, 139.26,138.11, 130.13, 127.65, 127.12, 124.43, 123.70, 122.20, 120.95, 112.25.MS (ESI) [M + H]⁺ = 305 10 ¹H NMR (300 MHz, CDCl₃) δ 9.10 (d, J = 2.5,1H), 8.83 (d, J = 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J = 1.3,5.0, 1H), 7.85-7.79 (m, 1H), 7.52 (pd, J = 1.5, 6.9, 2H), 7.33 (s, 1H),7.04 (dd, J = 1.2, 7.9, 1H), 6.81 (dd, J = 5.1, 7.9, 1H), 3.95 (s, 3H)11 MS (ESI) [M + H]⁺ = 290 12 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (d, J =2.7, 1H), 8.86 (d, J = 2.5, 1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J =2.7, 9.2, 1H), 8.08 (d, J = 8.5, 1H), 7.83 (d, J = 8.5, 1H), 7.71-7.63(m, 2H), 7.57 (t, J = 7.4, 2H), 6.82 (d, J = 9.1, 1H) 13 ¹H NMR (300MHz, CDCl₃) δ 8.83 (d, J = 2.6, 1H), 8.37 (d, J = 2.3, 1H), 8.00 (d, J =8.2, 1H), 7.71 (d, J = 7.7, 1H), 7.59-7.51 (m, 1H), 7.46 (dd, J = 7.3,15.1, 2H), 6.71 (d, J = 8.3, 1H), 6.67 (d, J = 7.4, 1H), 2.49 (s, 3H)¹³C NMR (75 MHz, CDCl₃) δ 157.13, 154.59, 145.81, 144.43, 138.78,134.54, 129.22, 128.86, 127.41, 127.27, 121.48, 115.41, 106.50, 24.18.MS (ESI) [M + H]⁺ = 236 14 MS (ESI) [M + H]⁺ = 266 15 MS (ESI) [M + H]⁺= 290 16 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 4.2, 1H), 8.04(dd, J = 4.7, 8.7, 2H), 7.92 (d, J = 2.4, 1H), 7.59 (dd, J = 2.5, 9.1,1H), 7.47 (t, J = 7.8, 1H), 7.35 (dd, J = 4.2, 8.3, 1H), 6.87 (s, 1H),6.81 (d, J = 8.2, 1H), 6.70 (d, J = 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M +H]⁺ = 236 18 ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 59.9, 2H), 7.76 (d,J = 8.6, 1H), 7.58 (t, J = 8.3, 2H), 7.42 (d, J = 7.8, 1H), 7.09 (t, J =7.7, 1H), 6.95 (d, J = 8.7, 1H), 6.71 (d, J = 7.3, 1H), 2.38 (s, 3H) 21¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.89 (d,J = 8.3, 1H), 7.79 (s, 1H), 7.63 (d, J = 8.0, 1H), 7.56 (d, J = 7.3,1H), 7.38 (s, 1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J = 4.9, 1H), 2.44(s, 6H) 22 ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 8.4, 1H), 8.28 (d, J =5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76-7.70 (m, 1H), 7.62(d, J = 8.0, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.32 (t, J = 7.4,1H), 6.95 (dd, J = 5.1, 6.5, 1H), 2.45 (s, 3H) 23 ¹H NMR (300 MHz,CDCl₃) δ 8.64 (d, J = 8.4, 1H), 8.55 (d, J = 2.1, 1H), 8.03 (s, 1H),7.90 (d, J = 8.5, 4H), 7.66 (t, J = 7.6, 1H), 7.44 (t, J = 7.6, 1H),7.06 (s, 1H), 2.67 (s, 4H) 24 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (d, J =8.9, 1H), 8.53 (d, J = 1.7, 1H), 7.94 (dd, J = 2.2, 8.9, 1H), 7.92-7.84(m, 2H), 7.67 (d, J = 8.6, 2H), 7.65-7.58 (m, 1H), 7.40 (t, J = 7.4,1H), 2.49 (s, 3H) 25 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 5.2, 1H),8.10 (s, 1H), 7.90 (d, J = 8.8, 1H), 7.79 (d, J = 9.0, 1H), 7.66 (d, J =2.2, 1H), 7.55 (dd, J = 2.3, 8.9, 1H), 7.39 (d, J = 9.0, 1H), 6.79 (d, J= 5.2, 1H), 2.42 (s, 3H) MS (ESI) [M + H]⁺ = 270 26 ¹H NMR (300 MHz,CDCl₃) δ 8.06 (d, J = 8.3, 1H), 7.70 (d, J = 9.0, 1H), 7.64 (d, J = 8.9,1H), 7.49 (t, J = 7.9, 2H), 7.40 (dd, J = 2.3, 8.9, 1H), 7.18 (d, J =8.9, 1H), 6.68 (d, J = 7.4, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 270 27¹H NMR (300 MHz, CDCl₃) δ 9.17 (d, J = 2.5, 1H), 8.71 (s, 1H), 8.49 (dd,J = 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9, 2H), 7.74-7.64 (m,1H), 7.48 (dd, J = 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H) 28 ¹H NMR(300 MHz, CDCl₃) δ 8.64-8.51 (m, 3H), 8.18 (d, J = 9.0, 1H), 7.93 (d, J= 8.4, 1H), 7.79 (d, J = 8.1, 1H), 7.73-7.64 (m, 1H), 7.51-7.41 (m, 1H),7.00 (dd, J = 4.6, 8.2, 1H), 6.75 (dd, J = 4.6, 8.3, 0H) 29 ¹H NMR (300MHz, CDCl₃) δ 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J = 8.2, 1H), 7.76(dd, J = 6.6, 25.5, 2H), 7.38 (d, J = 7.2, 1H), 7.04 (d, J = 4.4, 1H) 30¹H NMR (300 MHz, CDCl₃) δ 8.46 (dd, J = 1.9, 5.0, 1H), 7.87 (dd, J =2.0, 7.6, 1H), 7.82 (d, J = 7.3, 1H), 7.60 (t, J = 7.3, 2H), 7.43-7.33(m, 1H), 6.90 (dd, J = 5.0, 7.6, 1H), 2.64 (s, 3H) 31 ¹H NMR (300 MHz,CDCl₃) δ 8.44 (d, J = 9.1, 1H), 8.17 (d, J = 4.8, 1H), 8.03 (d, J = 9.1,1H), 7.78 (d, J = 8.4, 1H), 7.68 (d, J = 8.0, 1H), 7.62-7.54 (m, 1H),7.39 (d, J = 7.3, 1H), 7.32 (t, J = 7.5, 1H), 6.82 (dd, J = 5.0, 7.3,1H), 2.31 (s, 3H) MS (ESI) [M + H]⁺ = 236 32 ¹H NMR (300 MHz, CDCl₃) δ8.23 (d, J = 8.5, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.9, 1H), 7.82 (d, J =8.4, 1H), 7.62 (d, J = 8.3, 1H), 7.56 (d, J = 7.3, 1H), 7.50 (dd, J =1.8, 8.5, 1H), 7.37-7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M + H]⁺ = 23633 ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.32 (d, J = 5.0, 1H), 7.95(d, J = 8.8, 1H), 7.84 (d, J = 8.3, 1H), 7.60 (dd, J = 7.4, 14.1, 2H),7.32 (t, J = 7.5, 1H), 7.04 (dd, J = 5.0, 9.0, 2H) MS (ESI) [M + H]⁺ =247 34 ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.45 (d, J = 8.6, 1H),8.01 (d, J = 8.8, 1H), 7.87 (dd, J = 2.5, 8.5, 2H), 7.72-7.56 (m, 2H),7.39 (d, J = 9.0, 2H) MS (ESI) [M + H]⁺ = 290 35 ¹H NMR (300 MHz, CDCl₃)δ 8.32 (d, J = 9.1, 1H), 8.07 (d, J = 4.8, 1H), 7.93 (d, J = 9.1, 1H),7.59 (t, J = 7.9, 1H), 7.52 (d, J = 8.0, 1H), 7.36 (d, J = 7.2, 1H),7.14 (t, J = 7.8, 1H), 6.77 (dd, J = 5.0, 7.3, 1H), 2.29 (s, 3H) MS(ESI) [M + H]⁺ = 270 36 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 7.2, 1H),8.01 (s, 1H), 7.82 (d, J = 8.9, 1H), 7.62 (d, J = 7.6, 1H), 7.53 (dd, J= 1.8, 8.6, 1H), 7.46 (d, J = 7.9, 1H), 7.12 (t, J = 7.8, 1H), 7.05 (d,J = 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M + H]⁺ = 270 37 ¹H NMR (300 MHz,CDCl₃) δ 9.08 (d, J = 8.5, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J =8.1, 2H), 7.77 (d, J = 7.2, 1H), 7.62 (d, J = 7.6, 1H), 7.35-7.24 (m,1H), 7.12 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 324 38 ¹H NMR (300 MHz,CDCl₃) δ 8.69 (d, J = 9.1, 1H), 7.97 (d, J = 9.1, 1H), 7.80-7.74 (m,1H), 7.70 (d, J = 8.4, 1H), 7.59 (d, J = 8.0, 1H), 7.54-7.45 (m, 1H),7.22 (t, J = 7.5, 1H), 6.87 (d, J = 7.9, 1H), 6.68 (dd, J = 5.0, 7.9,1H), 3.73 (s, 3H) MS (ESI) [M + H]⁺ = 252 39 ¹H NMR (300 MHz, CDCl₃) δ8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H),7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H),6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7,3H) 40 ¹H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.12 (d, J = 2.3, 1H),8.50 (d, J = 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.80(s, 1H), 7.64 (t, J = 7.7, 1H), 7.45 (t, J = 7.8, 1H) 41 ¹H NMR (300MHz, CDCl₃) δ 8.52 (dd, J = 2.8, 8.6, 1H), 8.35 (s, 1H), 8.15 (d, J =2.3, 1H), 7.94 (d, J = 8.8, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (d, J =7.8, 1H), 7.59 (d, J = 7.2, 1H), 7.50-7.40 (m, 1H), 7.33 (t, J = 7.4,1H), 7.11 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 240 42 ¹H NMR (300 MHz,CDCl₃) δ 8.55 (d, J = 6.8, 1H), 8.01 (d, J = 8.9, 2H), 7.82 (dd, J =9.1, 17.3, 2H), 7.69 (d, J = 8.0, 1H), 7.63 (t, J = 7.6, 1H), 7.37 (t, J= 7.5, 1H), 7.32-7.18 (m, 2H) MS (ESI) [M + H]⁺ = 290 43 ¹H NMR (300MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J = 4.1, 9.3, 1H), 8.31 (d, J =2.9, 1H), 8.20 (d, J = 8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J = 8.9,1H), 7.32 (t, J = 7.8, 1H) ¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32,153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49, 126.86,125.29, 125.14, 125.04, 123.36, 114.91, 113.36. MS (ESI) [M + H]⁺ = 27444 ¹H NMR (300 MHz, CDCl₃) δ 11.09 (s, 1H), 8.78 (d, J = 9.0, 1H), 8.42(dd, J = 1.9, 4.7, 1H), 8.28 (dd, J = 1.9, 7.8, 1H), 8.11 (d, J = 9.1,1H), 7.73 (d, J = 7.5, 1H), 7.65 (d, J = 8.1, 1H), 7.27 (dd, J = 6.4,9.2, 1H), 6.88 (dd, J = 4.8, 7.8, 1H) MS (ESI) [M + H]⁺ = 300 46 ¹H NMR(300 MHz, CDCl₃) δ 8.59 (d, J = 8.3, 1H), 7.73 (d, J = 8.3, 1H), 7.57(s, 1H), 7.51 (t, J = 7.9, 1H), 7.43 (t, J = 9.2, 2H), 7.17 (t, J = 7.4,1H), 6.67 (d, J = 7.4, 1H), 2.36 (s, 3H), 2.28 (s, 3H) 47 ¹H NMR (300MHz, MeOD) δ 8.99 (s, 1H), 8.76 (d, J = 9.2, 1H), 8.32 (d, J = 8.7, 1H),8.22 (d, J = 8.6, 1H), 8.11 (d, J = 7.8, 1H), 8.01 (t, J = 7.1, 1H),7.76 (t, J = 7.4, 1H), 7.55-7.43 (m, 2H) MS (ESI) [M + H]⁺ = 247 48 ¹HNMR (300 MHz, MeOD) δ 8.48 (d, J = 9.1, 1H), 8.40 (d, J = 6.7, 1H), 7.94(d, J = 8.4, 1H), 7.90 (d, J = 7.8, 1H), 7.54 (t, J = 8.0, 1H), 7.38 (d,J = 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H) MS (ESI) [M + H]⁺ = 270 49 ¹HNMR (300 MHz, CDCl₃) δ 9.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.1,1H), 7.87 (d, J = 8.9, 1H), 7.71 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.19 (t, J = 7.8, 1H), 7.05 (d, J = 8.9, 1H), 6.84 (d, J = 5.1,1H), 2.76 (q, J = 7.6, 2H), 1.37 (t, J = 7.6, 3H) 50 ¹H NMR (300 MHz,CDCl₃) δ 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J =6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J =8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t,J = 7.7, 3H) 51 ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 8.06 (s, 1H),7.89 (d, J = 8.7, 1H), 7.71 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H),7.20 (t, J = 7.7, 1H), 7.02 (d, J = 8.8, 1H), 6.67 (s, 1H), 2.43 (s,3H), 2.39 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.15, 153.17, 152.82,150.16, 143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62,114.47, 111.02, 24.13, 21.70. MS (ESI) [M + H]⁺ = 284 52 ¹H NMR (300MHz, CDCl₃) δ 8.89 (d, J = 8.8, 1H), 8.05 (d, J = 8.8, 1H), 8.01 (s,1H), 7.93 (d, J = 8.8, 1H), 7.79 (d, J = 7.5, 1H), 7.64 (d, J = 8.0,1H), 7.32 (t, J = 7.8, 1H), 7.13 (d, J = 8.8, 1H), 2.67 (s, 3H) 53 ¹HNMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.33 (d, J = 5.7, 1H), 8.13 (d, J =5.2, 1H), 8.00 (d, J = 8.8, 1H), 7.76 (d, J = 7.4, 1H), 7.60 (d, J =8.0, 1H), 7.29 (d, J = 7.9, 1H), 7.07 (d, J = 8.9, 1H), 6.97 (d, J =4.8, 1H) 54 MS (ESI) [M + H]⁺ = 250 55 ¹H NMR (300 MHz, CDCl₃) δ 8.19(s, 1H), 7.90 (d, J = 9.0, 1H), 7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.33 (d, J = 7.4, 1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5,1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.7, 3H)56 ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.63(d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4, 1H), 7.14 (t,J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47(s, 3H), 1.25 (dd, J = 7.5, 15.5, 3H) 57 MS (ESI) [M + H]⁺ = 253 58 MS(ESI) [M + H]⁺ = 314-316 59 ¹H NMR (300 MHz, CDCl₃) δ 8.91 (d, J = 1.7,1H), 8.46 (d, J = 8.8, 1H), 8.28 (dd, J = 2.0, 8.8, 1H), 8.23 (s, 1H),8.03 (d, J = 8.8, 1H), 7.88 (d, J = 8.3, 1H), 7.70 (d, J = 8.0, 1H),7.67-7.58 (m, 1H), 7.38 (t, J = 7.4, 1H), 7.32 (d, J = 8.8, 2H), 3.91(s, 3H) 60 ¹H NMR (300 MHz, CDCl₃) δ 8.94 (d, J = 8.9, 1H), 8.91 (d, J =1.8, 1H), 8.37 (dd, J = 2.2, 8.8, 1H), 8.04 (d, J = 8.9, 2H), 7.77 (d, J= 7.5, 1H), 7.62 (d, J = 7.2, 1H), 7.30 (t, J = 7.8, 2H), 7.19 (d, J =8.8, 2H), 3.92 (s, 3H) 61 ¹H NMR (300 MHz, CDCl₃) δ 8.96 (d, J = 8.8,1H), 8.85 (d, J = 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J = 8.0,1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4, 2H), 7.53 (d, J =8.4, 1H), 7.31 (t, J = 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H) MS (ESI)[M + H]⁺ = 294 62 ¹H NMR (300 MHz, CDCl₃) δ 11.02 (s, 1H), 8.75 (d, J =9.2, 1H), 8.44 (d, J = 3.7, 1H), 8.31 (d, J = 7.9, 1H), 8.10 (d, J =9.0, 1H), 7.72 (d, J = 7.5, 1H), 7.64 (d, J = 8.2, 1H), 7.27 (d, J =8.1, 1H), 6.88 (dd, J = 4.7, 7.8, 1H), 3.97 (s, 3H) MS (ESI) [M + H]⁺ =314 63 MS (ESI) [M + H]⁺ = 266 64 ¹H NMR (300 MHz, DMSO) δ 10.38 (s,1H), 8.56 (s, 1H), 8.28 (d, J = 9.1, 1H), 8.20-8.03 (m, 3H), 7.50 (d, J= 8.7, 1H), 7.45 (d, J = 8.0, 1H), 6.88 (d, J = 4.4, 1H), 2.37 (s, 3H)65 MS (ESI) [M + H]⁺ = 314-316 66 MS (ESI) [M + H]⁺ = 250 67 ¹H NMR (300MHz, DMSO) δ 10.51 (s, 1H), 8.83 (d, J = 2.3, 1H), 8.62 (d, J = 9.3,1H), 8.24 (dd, J = 2.7, 9.1, 1H), 7.96 (d, J = 8.9, 1H), 7.81 (d, J =7.8, 1H), 7.67 (t, J = 7.6, 1H), 7.45 (d, J = 11.2, 2H), 3.86 (s, 3H),2.62 (s, 3H) MS (ESI) [M + H]⁺ = 294 68 ¹H NMR (300 MHz, CDCl₃) δ 9.57(s, 1H), 8.44 (d, J = 4.8, 1H), 8.05 (d, J = 8.8, 1H), 7.86 (s, 1H),7.80 (d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.31 (t, J = 7.8, 1H),7.19 (d, J = 4.3, 1H), 7.04 (d, J = 8.8, 1H) 69 ¹H NMR (300 MHz, CDCl₃)δ 9.12 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.71 (d, J = 7.5, 1H), 7.57 (d, J= 7.8, 1H), 7.40 (s, 1H), 7.25 (d, J = 10.2, 2H), 7.17 (s, 1H), 7.05 (s,1H) 70 ¹H NMR (300 MHz, CDCl₃) δ 9.07 (d, J = 8.5, 1H), 7.97 (d, J =8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H), 7.75 (dd, J = 1.1, 7.5,1H), 7.62-7.55 (m, 1H), 7.31 (d, J = 7.6, 1H), 7.27 (t, J = 7.8, 1H),7.08 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 274 71 MS (ESI) [M + H]⁺ = 27472 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3,1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.57 (d, J = 7.9, 2H), 7.52 (d, J= 7.1, 1H), 7.28 (t, J = 7.4, 1H), 2.74 (q, J = 7.6, 2H), 2.42 (s, 3H),1.31 (t, J = 7.6, 3H) MS (ESI) [M + H]⁺ = 264 73 ¹H NMR (300 MHz, CDCl₃)δ 8.91 (dd, J = 3.8, 9.0, 1H), 8.11 (d, J = 2.9, 1H), 7.81 (d, J = 8.3,1H), 7.71 (s, 1H), 7.56 (dd, J = 7.4, 14.1, 2H), 7.51-7.42 (m, 1H), 7.29(d, J = 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 254 74 ¹H NMR (300MHz, CDCl₃) δ 8.96 (d, J = 8.3, 1H), 8.49 (s, 1H), 7.89 (dd, J = 1.9,9.0, 1H), 7.82 (d, J = 8.2, 1H), 7.72 (s, 1H), 7.57 (t, J = 8.7, 3H),7.33 (t, J = 7.4, 1H), 2.37 (s, 3H) MS (ESI) [M + H]⁺ = 304 75 ¹H NMR(300 MHz, CDCl₃) δ 7.83 (d, J = 9.0, 1H), 7.69 (dd, J = 1.3, 7.6, 1H),7.53 (dd, J = 1.2, 8.0, 1H), 7.42 (d, J = 8.9, 2H), 7.15 (t, J = 7.8,1H), 6.89 (d, J = 8.9, 2H), 6.79 (d, J = 8.9, 2H), 2.97 (s, 6H) 77 ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, J = 8.8, 1H), 7.70 (d, J = 7.6, 1H),7.59 (d, J = 8.6, 2H), 7.52 (d, J = 7.3, 1H), 7.16 (t, J = 7.7, 1H),6.94 (d, J = 8.4, 3H), 6.86 (d, J = 8.8, 1H), 3.82 (s, 3H) ¹³C NMR (75MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99,126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74. MS (ESI) [M + H]⁺= 285 78 ¹H NMR (300 MHz, CDCl₃) δ 7.80 (t, J = 7.6, 2H), 7.64 (d, J =8.9, 2H), 7.61-7.55 (m, 1H), 7.33 (t, J = 7.6, 1H), 7.19 (d, J = 8.7,2H), 2.59 (s, 3H) 79 ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.4, 1H),7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.57 (dd, J = 1.1, 8.0, 1H), 7.51 (ddd,J = 1.5, 7.0, 8.4, 1H), 7.29-7.21 (m, 1H), 6.96-6.90 (m, 2H), 3.82 (s,3H), 2.35 (s, 3H) 80 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9 Hz, 2H),7.84 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57(t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H),6.53 (s, 1H), 2.42 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25,143.86, 139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88,120.44, 119.95, 17.77. MS (ESI) [M + H]⁺ = 319 81 ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, J = 8.3, 1H), 7.66 (d, J = 8.5, 3H), 7.55 (d, J = 7.8,1H), 7.48 (t, J = 7.6, 1H), 7.20 (d, J = 7.2, 1H), 6.80 (d, J = 8.8,2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35 (s, 3H) 82 ¹H NMR (300 MHz, CDCl₃)δ 7.92 (d, J = 8.9, 1H), 7.82-7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59(t, J = 7.6, 1H), 7.30 (dd, J = 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s,1H), 6.84 (d, J = 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M + H]⁺ = 319 83 ¹HNMR (300 MHz, CDCl₃) δ 7.93-7.86 (m, 1H), 7.85 (s, 1H), 7.82 (d, J =8.4, 1H), 7.59 (dd, J = 8.2, 15.5, 2H), 7.44-7.38 (m, 1H), 7.29 (dd, J =8.3, 16.8, 2H), 6.91 (d, J = 9.0, 1H), 6.87 (d, J = 8.3, 1H) MS (ESI)[M + H]⁺ = 305 84 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 8.1, 1H), 7.92(d, J = 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J = 7.6, 1H), 7.58 (d,J = 7.3, 1H), 7.30 (dd, J = 6.8, 14.8, 3H), 7.02 (t, J = 7.8, 1H), 6.89(d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 305 86 ¹H NMR (300 MHz, CDCl₃) δ7.93 (d, J = 8.9, 1H), 7.83 (d, J = 8.3, 1H), 7.70 (d, J = 12.0, 1H),7.61 (dd, J = 7.9, 18.1, 2H), 7.32 (d, J = 7.9, 1H), 7.31-7.25 (m, 1H),7.21 (t, J = 6.5, 1H), 6.92 (d, J = 8.9, 1H), 6.79-6.68 (m, 1H) MS (ESI)[M + H]⁺ = 239 87 ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 7.76 (d, J =8.9, 1H), 7.67 (d, J = 7.5, 1H), 7.51 (d, J = 8.2, 1H), 7.45 (d, J =7.9, 1H), 7.28 (d, J = 8.2, 1H), 7.14 (t, J = 7.8, 1H), 6.86 (d, J =10.1, 1H), 6.76 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 339 88 ¹H NMR (300MHz, CDCl₃) δ 8.11 (dt, J = 2.1, 12.1, 1H), 7.76 (d, J = 8.9, 1H), 7.66(dd, J = 1.2, 7.6, 1H), 7.45 (dd, J = 1.1, 8.0, 1H), 7.22 (dd, J = 1.4,7.2, 2H), 7.18 (d, J = 7.6, 1H), 7.12 (d, J = 7.8, 1H), 6.75 (d, J =8.9, 1H), 6.69 (d, J = 7.9, 1H) MS (ESI) [M + H]⁺ = 273 89 ¹H NMR (300MHz, DMSO) δ 11.38 (s, 1H), 8.41 (d, J = 9.1, 1H), 7.93 (d, J = 7.8,1H), 7.80 (dt, J = 8.1, 20.9, 4H), 7.50 (d, J = 7.8, 3H), 7.36 (d, J =9.3, 1H) 90 ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 9.1, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (dd, J = 1.2, 7.6, 1H), 7.48 (dd, J = 1.1, 8.0, 1H),7.18 (s, 3H), 6.89 (s, 1H), 6.75 (d, J = 8.9, 1H) ¹³C NMR (75 MHz,CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25, 131.13, 130.13, 126.55,125.42, 123.45, 122.50, 122.17, 120.49, 119.10, 113.24. MS (ESI) [M +H]⁺ = 339 91 ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.54 (s, 1H), 8.46(d, J = 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H),7.67 (d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9,1H) 92 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J =8.3, 1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.55 (dd, J = 7.5, 14.4, 2H),7.29 (d, J = 7.8, 1H), 6.80 (d, J = 7.4, 1H) 93 ¹H NMR (300 MHz, CDCl₃)δ 9.21 (dd, J = 1.5, 8.4, 1H), 7.85 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.58(d, J = 7.8, 1H), 7.53 (dd, J = 1.3, 8.3, 1H), 7.40-7.35 (m, 1H), 7.32(dd, J = 1.1, 4.6, 1H), 7.31-7.24 (m, 2H), 7.04 (s, 1H), 7.02-6.94 (m,1H), 2.38 (s, 3H) 94 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 8.7, 1H),7.83 (d, J = 8.9, 1H), 7.63 (d, J = 7.6, 1H), 7.48 (d, J = 8.0, 1H),7.13 (t, J = 7.8, 1H), 7.08 (s, 1H), 7.04 (s, 2H), 6.81 (d, J = 8.9,2H), 2.27 (s, 3H) MS (ESI) [M + H]⁺ = 353 95 ¹H NMR (300 MHz, MeOD) δ8.42 (s, 1H), 7.94 (d, J = 7.9, 1H), 7.83 (d, J = 8.1, 1H), 7.78 (d, J =7.1, 1H), 7.72 (d, J = 8.7, 2H), 7.58 (d, J = 8.2, 3H), 2.60 (s, 3H) MS(ESI) [M + H]⁺ = 319 96 ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J = 8.9, 1H),7.70 (d, J = 8.9, 1H), 7.64 (d, J = 8.9, 2H), 7.59 (d, J = 2.1, 1H),7.50 (dd, J = 2.3, 8.9, 1H), 7.19 (d, J = 8.6, 2H), 6.85 (d, J = 8.9,1H) MS (ESI) [M + H]⁺ = 281 97 ¹H NMR (300 MHz, MeOD) δ 8.11 (d, J =8.4, 1H), 7.81 (s, 2H), 7.62 (d, J = 8.7, 3H), 7.51 (d, J = 8.3, 2H),7.12 (s, 1H), 2.77 (s, 3H) MS (ESI) [M + H]⁺ = 319 98 MS (ESI) [M + H]⁺= 383-385 99 MS (ESI) [M + H]⁺ = 320 100 MS (ESI) [M + H]⁺ = 316 101 ¹HNMR (300 MHz, CDCl₃) δ 7.82 (d, J = 8.9, 1H), 7.70-7.63 (m, 1H), 7.51(dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H),6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84-1.68 (m, 3H), 1.49(dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) MS (ESI) [M + H]⁺ = 327102 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J = 8.5,1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 313 103 MS (ESI) [M + H]⁺ =334 104 ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 2.5, 1H), 7.89 (d, J =8.8, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (dd, J = 2.5, 8.9, 1H), 7.53 (d, J= 8.0, 1H), 7.23 (dd, J = 6.2, 14.0, 2H), 7.04 (s, 1H), 6.81 (d, J =8.8, 1H) MS (ESI) [M + H]⁺ = 373 105 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (d,J = 2.6, 1H), 8.45 (d, J = 2.3, 1H), 8.01 (d, J = 8.1, 1H), 7.71 (d, J =7.8, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6, 1H), 7.51-7.45 (m, 2H),7.45-7.36 (m, 1H), 6.72-6.62 (m, 2H), 2.48 (s, 3H) 13C NMR (75 MHz,CDCl₃) δ 157.18, 154.80, 145.42, 143.80, 138.17, 135.04, 128.88, 128.76,127.17, 127.04, 120.69, 115.22, 106.73, 24.38 106 ¹H NMR (300 MHz, DMSO)δ 10.24 (s, 1H), 9.06 (d, J = 2.3, 1H), 8.65 (d, J = 1.8, 1H), 8.60 (d,J = 8.3, 1H), 8.56 (d, J = 4.5, 1H), 7.97 (dd, J = 8.2, 14.4, 2H), 7.69(t, J = 6.9, 1H), 7.59 (t, J = 7.4, 1H), 7.08 (dd, J = 4.6, 8.3, 1H) MS(ESI) [M + H]⁺ = 267 107 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5,4.3, 1H), 8.06 (dd, J = 10.8, 18.4, 3H), 7.93 (d, J = 2.4, 1H), 7.57(dd, J = 2.4, 9.0, 1H), 7.39 (ddd, J = 3.1, 8.3, 12.5, 3H), 6.93 (d, J =8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 ¹H NMR (300 MHz, CDCl₃) δ 8.72(dd, J = 1.6, 4.2, 1H), 8.61 (d, J = 2.4, 1H), 8.11 (d, J = 8.3, 1H),8.00 (d, J = 9.0, 1H), 7.91 (dd, J = 1.2, 5.0, 1H), 7.69 (dd, J = 2.4,9.1, 1H), 7.35-7.26 (m, 2H), 7.01 (dd, J = 1.2, 7.9, 1H), 6.77 (dd, J =5.1, 7.8, 1H), 3.93 (s, 3H) 109 ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s, 1H),8.21 (s, 2H), 7.94 (d, J = 8.9, 1H), 7.79 (d, J = 9.2, 1H), 7.67 (d, J =2.3, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.34 (d, J = 8.9, 1H) MS (ESI)[M + H]⁺ = 257 110 1H NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.33-8.21(m, 2H), 8.05 (d, J = 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J= 1.1, 7.8, 1H), 7.61 (s, 1H), 7.30-7.22 (m, 3H), 7.16 (d, J = 8.8, 1H).MS (ESI) [M + H]⁺ = 301-303 111 ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J =8.9, 1H), 7.70-7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J =7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J =6.5, 2H), 1.84-1.68 (m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J =7.4, 3H) 112 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J= 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) ¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48,142.18, 138.20, 137.55, 135.74, 129.71, 126.99, 125.35, 123.84, 114.75.MS (ESI) [M + H]⁺ = 255 113 ¹H NMR (300 MHz, CDCl₃) δ 9.74 (s, 1H), 8.20(s, 2H), 8.03 (d, J = 8.6, 1H), 7.87 (d, J = 7.6, 1H), 7.80 (s, 1H),7.70 (d, J = 8.0, 1H), 7.63 (t, J = 7.7, 1H), 7.37 (t, J = 7.4, 1H),7.30 (d, J = 8.7, 1H) 114 ¹H NMR (300 MHz, CDCl₃) δ 9.67 (s, 1H),8.34-8.12 (m, 2H), 7.84 (d, J = 8.0, 2H), 7.70-7.54 (m, 1H), 7.38 (t, J= 7.6, 1H), 7.17 (s, 1H), 2.61 (s, 3H) MS (ESI) [M + H]⁺ = 237 115 ¹HNMR (300 MHz, CDCl₃) δ 10.15 (s, 1H), 8.24-8.12 (m, 2H), 7.79 (s, 1H),7.71 (s, 1H), 7.55 (t, J = 8.3, 2H), 7.30 (t, J = 7.9, 1H), 2.38 (s, 3H)MS (ESI) [M + H]⁺ = 237 116 MS (ESI) [M + H]⁺ = 240 117 MS (ESI) [M +H]⁺ = 253 118 MS (ESI) [M + H]⁺ = 222 119 MS (ESI) [M + H]⁺ = 256 121 MS(ESI) [M + H]⁺ = 222 124 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.95(dd, J = 1.3, 8.2, 1H), 7.87-7.78 (m, 3H), 7.70-7.61 (m, 1H), 7.55-7.47(m, 1H), 7.26 (dd, J = 2.4, 6.5, 3H), 6.90 (s, 1H) MS (ESI) [M + H]⁺ =306 125 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.03 (d, J = 9.5, 1H),7.92 (d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.61 (t, J = 7.3, 1H),7.46 (t, J = 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126 ¹HNMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.2,1H), 7.84 (d, J = 8.2, 1H), 7.65 (t, J = 7.4, 1H), 7.53 (d, J = 7.1,1H), 7.48 (d, J = 7.2, 1H), 7.35 (t, J = 8.2, 1H), 7.22 (s, 1H), 6.94(d, J = 8.1, 1H) 127 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (dd, J = 1.0, 8.3,1H), 8.47 (s, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H),7.72-7.61 (m, 1H), 7.57-7.47 (m, 1H), 7.42-7.36 (m, 1H), 7.33 (d, J =10.0, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H) 128 ¹H NMR (300 MHz, CDCl₃) δ9.17 (s, 1H), 8.68 (d, J = 9.1, 1H), 8.64 (d, J = 4.8, 2H), 8.15 (d, J =9.1, 1H), 7.87 (d, J = 8.4, 1H), 7.76 (d, J = 8.1, 1H), 7.64 (t, J =7.7, 1H), 7.39 (t, J = 7.5, 1H), 6.87 (t, J = 4.8, 1H) ¹³C NMR (75 MHz,CDCl3) δ 158.34, 138.07, 129.85, 127.63, 127.31, 124.34, 114.20, 113.90.129 ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.73 (d, J = 21.2, 3H), 8.17(s, 1H), 7.73 (d, J = 20.3, 2H), 7.28 (d, J = 9.6, 2H), 6.91 (s, 1H) 130¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 8.64 (d, J = 4.8, 2H), 8.52 (s,1H), 7.89 (dd, J = 8.5, 14.6, 2H), 7.63 (t, J = 7.5, 1H), 7.41 (t, J =7.4, 1H), 6.86 (t, J = 4.8, 1H), 2.74 (s, 3H) MS (ESI) [M + H]⁺ = 237132 ¹H NMR (300 MHz, CDCl₃) δ 8.86 (d, J = 2.6, 1H), 8.70 (d, J = 2.5,1H), 8.32 (d, J = 1.1, 1H), 8.25-8.21 (m, 1H), 8.10 (d, J = 2.7, 1H),8.06 (d, J = 8.3, 1H), 7.82 (dd, J = 1.2, 7.9, 1H), 7.66-7.51 (m, 3H),6.89 (s, 1H) 135 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 8.71 (s, 1H),8.54 (d, J = 8.4, 1H), 8.37 (dd, J = 1.0, 4.9, 1H), 7.96 (d, J = 8.2,1H), 7.85 (d, J = 8.3, 1H), 7.82-7.74 (m, 1H), 7.66 (t, J = 7.6, 1H),7.52 (dd, J = 7.0, 8.1, 1H), 7.02 (dd, J = 5.0, 7.2, 1H) MS (ESI) [M +H]⁺ = 223 136 ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30(s, 1H), 8.20 (d, J = 5.1, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2,1H), 7.64 (t, J = 7.6, 1H), 7.49 (t, J = 8.1, 1H), 6.83 (d, J = 5.0,1H), 2.43 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55,147.40, 140.93, 139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70,113.75, 21.87. MS (ESI) [M + H]⁺ = 237 137 ¹H NMR (300 MHz, DMSO) δ11.10 (s, 1H), 9.03 (s, 1H), 8.82-8.75 (m, 1H), 8.56 (d, J = 8.9, 1H),8.24 (dd, J = 2.3, 8.9, 1H), 7.96 (dd, J = 1.2, 8.2, 1H), 7.87 (dd, J =1.0, 8.3, 1H), 7.79-7.71 (m, 1H), 7.61 (ddd, J = 1.4, 7.0, 8.3, 1H) MS(ESI) [M + H]⁺ = 248 138 ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.53(s, 1H), 8.20 (d, J = 8.3, 1H), 7.93 (d, J = 8.2, 1H), 7.81 (d, J = 8.3,1H), 7.62 (td, J = 3.4, 8.1, 2H), 7.53-7.43 (m, 1H), 6.83 (d, J = 7.4,1H), 2.48 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.86, 152.27, 148.40,140.92, 139.70, 139.00, 138.35, 130.42, 129.13, 127.14, 126.27, 117.76,110.01, 24.15. MS (ESI) [M + H]⁺ = 237 139 ¹H NMR (300 MHz, CDCl₃) δ8.53 (s, 1H), 8.20 (d, J = 4.8, 1H), 8.04 (d, J = 8.3, 1H), 7.92 (d, J =8.4, 1H), 7.87 (s, 1H), 7.79 (t, J = 7.6, 1H), 7.60 (t, J = 7.6, 1H),6.88 (d, J = 4.7, 1H), 2.46 (s, 3H) 140 ¹H NMR (300 MHz, CDCl₃) δ 9.93(s, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.1, 1H), 7.99 (s, 1H), 7.82 (d, J =8.2, 1H), 7.69 (t, J = 7.6, 1H), 7.59 (t, J = 8.2, 1H), 2.53 (s, 4H) 141¹H NMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 5.0,1H), 8.05 (d, J = 7.7, 1H), 7.87 (d, J = 7.0, 1H), 7.66 (dd, J = 7.4,16.9, 3H), 6.92 (d, J = 4.9, 1H), 2.58 (s, 3H) 143 ¹H NMR (300 MHz,DMSO) δ 8.85 (s, 1H), 8.42 (d, J = 5.3, 1H), 7.96 (d, J = 9.1, 1H), 7.44(s, 1H), 7.30 (s, 4H), 7.28-7.21 (m, 2H), 6.66 (d, J = 5.3, 1H), 2.99(s, 6H) ¹³C NMR (75 MHz, DMSO) δ 156.82, 150.25, 149.69, 143.79, 141.71,125.95, 122.33, 118.88, 117.37, 115.95, 109.39, 104.92, 43.57 MS (ESI)[M + H]+ = 348 144 MS (ESI) [M + H]⁺ = 390 145 MS (ESI) [M + H]⁺ = 252146 ¹H NMR (300 MHz, DMSO) δ 9.34 (s, 1H), 8.59 (d, J = 5.2, 1H), 8.53(s, 1H), 8.13 (d, J = 5.1, 1H), 7.98 (d, J = 9.0, 1H), 7.66 (d, J = 9.1,1H), 6.80 (d, J = 5.2, 1H), 6.76 (s, 1H), 6.69 (d, J = 4.9, 1H), 4.00(s, 3H), 2.26 (s, 3H) ¹³C NMR (75 MHz, DMSO) δ 161.31, 155.67, 151.63,150.25, 147.77, 147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60,111.41, 98.91, 55.78, 20.66. MS (ESI) [M + H]⁺ = 266 147 MS (ESI) [M +H]⁺ = 279 149 MS (ESI) [M + H]⁺ = 318 150 MS (ESI) [M + H]⁺ = 280 151 ¹HNMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 8.04 (d, J = 8.3, 1H), 7.82 (d, J =8.9, 1H), 7.74 (d, J = 8.9, 1H), 7.60 (t, J = 7.8, 2H), 7.50 (dd, J =2.3, 8.9, 1H), 7.36 (d, J = 8.9, 1H), 6.79 (d, J = 7.4, 1H), 2.75 (q, J= 7.6, 2H), 1.30 (t, J = 7.6, 3H). MS (ESI) [M + H]⁺ = 284 152 ¹H NMR(300 MHz, CDCl₃) δ 8.30 (d, J = 8.5, 1H), 8.08 (s, 1H), 7.90 (d, J =9.0, 1H), 7.77 (d, J = 8.9, 1H), 7.65 (d, J = 2.2, 1H), 7.55 (td, J =2.0, 8.8, 2H), 7.39 (d, J = 9.0, 1H), 2.31 (s, 3H). MS (ESI) [M + H]⁺ =270 153 ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J= 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67(d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H). MS(ESI) [M + H]⁺ = 324 154 ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.12 (d,J = 8.4, 1H), 7.73 (d, J = 8.2, 2H), 7.66 (d, J = 10.0, 1H), 7.53 (s,1H), 7.25 (s, 1H), 6.82 (s, 1H), 5.10 (s, 2H), 2.16 (s, 4H). MS (ESI)[M + H]⁺ = 285 155 ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 8.3, 1H), 7.61(s, 1H), 7.56 (d, J = 11.5, 2H), 7.44 (d, J = 8.3, 1H), 7.38 (d, J =7.8, 1H), 7.13 (t, J = 7.4, 1H), 6.80 (d, J = 8.7, 2H), 3.85 (t, J =6.5, 2H), 2.18 (s, 3H), 1.73-1.58 (m, 2H), 1.48-1.31 (m, 2H), 0.88 (t, J= 7.3, 3H) MS (ESI) [M + H]⁺ = 307 156 ¹H NMR (300 MHz, CDCl₃) δ 7.75(d, J = 9.1, 1H), 7.62 (d, J = 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48(dd, J = 2.4, 8.9, 1H), 7.30 (d, J = 8.9, 2H), 6.86 (d, J = 9.0, 1H),6.77 (d, J = 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M + H]⁺ =298 157 ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J = 2.6, 1H), 7.89 (d, J =8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J = 2.6, 8.8, 1H), 7.55 (d, J= 7.8, 1H), 7.20 (t, J = 7.8, 1H), 6.95 (d, J = 8.9, 1H), 6.84 (d, J =8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H) MS (ESI) [M + H]⁺ = 319 158 ¹H NMR(300 MHz, CDCl₃) δ 7.89 (d, J = 9.0, 1H), 7.70 (dd, J = 1.2, 7.5, 1H),7.56 (dd, J = 1.1, 8.0, 1H), 7.30 (d, J = 8.6, 1H), 7.20 (t, J = 7.8,1H), 6.71 (t, J = 5.9, 2H), 6.64 (d, J = 9.5, 1H). MS (ESI) [M + H]⁺ =354 159 ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, J = 2.6, 1H), 8.37 (d, J =2.6, 1H), 8.01 (d, J = 8.1, 1H), 7.91 (dd, J = 1.6, 4.9, 1H), 7.78-7.70(m, 1H), 7.58-7.43 (m, 2H), 7.09 (dd, J = 1.6, 7.6, 1H), 6.84 (dd, J =4.9, 7.6, 1H), 6.69 (s, 1H), 3.82-3.07 (m, 2H). 160 ¹H NMR (300 MHz,CDCl₃) δ 9.68-8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14 (d, J =5.0, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.8, 1H), 7.61 (d, J = 8.5, 1H),6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 ¹H NMR (300 MHz, CDCl₃) δ 9.98(s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 5.2, 1H), 7.94 (d, J =8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.63 (t, J = 7.5, 1H), 7.48 (t, J =7.5, 1H), 6.87 (d, J = 5.0, 1H), 2.74 (q, J = 7.6, 2H), 1.34 (t, J =7.6, 3H). MS (ESI) [M + H]⁺ = 251 162 ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s,1H), 8.70-8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.1,1H), 7.86 (d, J = 7.9, 1H), 7.68 (t, J = 8.2, 1H), 7.54 (t, J = 8.1,1H), 2.49 (s, 3H) MS (ESI) [M + H]⁺ = 315 163 ¹H NMR (300 MHz, CDCl₃) δ8.75 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.2, 1H), 7.84(d, J = 8.3, 1H), 7.64 (t, J = 8.2, 1H), 7.49 (t, J = 7.0, 1H), 6.69 (s,1H), 2.45 (s, 3H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 251 164 ¹H NMR (300MHz, DMSO) δ 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.24 (d, J =3.0, 1H), 7.90 (d, J = 8.2, 1H), 7.79 (d, J = 8.3, 1H), 7.69 (t, J =7.0, 1H), 7.52 (t, J = 7.4, 1H), 6.98 (d, J = 4.8, 1H), 5.45 (q, J =5.6, 1H), 4.58 (d, J = 5.7, 2H). MS (ESI) [M + H]⁺ = 253 165 ¹H NMR (300MHz, CDCl₃) δ 9.07 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H),8.09-8.01 (m, 1H), 7.94 (d, J = 8.4, 1H), 7.81-7.71 (m, 1H), 7.69-7.59(m, 1H), 2.80 (s, 3H) MS (ESI) [M + H]⁺ = 282 166 ¹H NMR (300 MHz,CDCl₃) δ 8.49 (d, J = 5.0, 1H), 7.77 (d, J = 9.0, 1H), 7.32 (d, J = 2.0,1H), 7.12 (d, J = 9.0, 2H), 6.99 (dd, J = 2.0, J = 9.0, 1H), 6.82 (d, J= 9.0, 2H), 6.57 (d, J = 5.0, 1H), 5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s,4H), 2.62 (s, 4H), 2.34 (s, 3H) 167 MS (ESI) [M + H]⁺ = 335 168 MS (ESI)[M + H]⁺ = 321

The following examples are provided as illustrations and in no way limitthe scope of this invention.

The following examples illustrate in detail the preparation of somecompounds according to the invention. The structures of the productsobtained have been confirmed by NMR spectra.

EXAMPLES

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a 1.1 molar ratio with respect to the compound of formula(III) in presence of Cs₂CO₃, in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), in a 2 mol %amount relative to the total amount of compound of formula (III), and inthe presence of Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (III). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, fitrered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compounds (6), (43), (77),(80), (90), (112) and (136).

According to route (B), the compound of formula (V) is placed in aprotic solvent such as tert-butanol. The compound of formula (VI) isthen added in a 1.1 molar ratio with respect to the compound of formula(V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %amount relative to the total amount of compound of formula (V), and inthe presence of a Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (V). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compound (106).

Example 1 Compound (6) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (1.5 g) and2-amino-4methylpyridine (904 mg), Pd(OAc)₂ (34 mg), XantPhos (88 mg) andCs₂CO₃ (7.0 g) in 30 mL of t-BuOH gave compound (6) (1.3 g).

¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J=8.8,2H), 7.78 (dd, J=7.7, 13.7, 2H), 7.46 (d, J=8.9, 1H), 7.31 (t, J=7.8,1H), 6.86 (d, J=4.3, 1H), 2.37 (s, 3H).

¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61, 148.37, 147.32, 142.65, 137.52,129.68, 129.47, 126.82, 125.06, 123.26, 118.36, 115.10, 113.31, 21.24.

MS (ESI) [M+H]⁺=270

Example 2 Compound (43) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (394 mg) and2-amino-5fluoropyridine (246 mg), Pd(OAc)₂ (9 mg), XantPhos (23 mg) andCs₂CO₃ (1.8 g) in 8 mL of t-BuOH gave compound (43) (320 mg).

¹H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J=4.1, 9.3, 1H), 8.31(d, J=2.9, 1H), 8.20 (d, J=8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J=8.9,1H), 7.32 (t, J=7.8, 1H).

¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32, 153.04, 150.17, 142.55, 137.73,135.06, 134.74, 129.58, 129.49, 126.86, 125.29, 125.14, 125.04, 123.36,114.91, 113.36.

MS (ESI) [M+H]⁺=274

Example 3 Compound (77) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (985 mg) andp-anisidine (677 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) and Cs₂CO₃ (4.6g) in 20 mL of t-BuOH gave compound (77) (629 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.8, 1H), 7.70 (d, J=7.6, 1H), 7.59(d, J=8.6, 2H), 7.52 (d, J=7.3, 1H), 7.16 (t, J=7.7, 1H), 6.94 (d,J=8.4, 3H), 6.86 (d, J=8.8, 1H), 3.82 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96,130.44, 129.99, 126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74.

MS (ESI) [M+H]⁺=285

Example 4 Compound (80) of the Table I

According to route (A), a mixture of 2-chloro-3methylquinoline (885 mg)and 4-(trifluoromethoxy)aniline (743 μL), Pd(OAc)₂ (22 mg), XantPhos (58mg) and Cs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (80) (1.3 g).

¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.9 Hz, 2H), 7.84 (d, J=8.3 Hz,1H), 7.78 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.32(t, J=7.4 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.53 (s, 1H), 2.42 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25, 143.86, 139.33, 136.83,128.93, 126.96, 126.71, 124.75, 123.56, 121.88, 120.44, 119.95, 17.77.

MS (ESI) [M+H]⁺=319

Example 5 Compound (90) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (984 mg) and4-(trifluoromethoxy)aniline (743 μL), Pd(OAc)₂ (22 mg), XantPhos (58 mg)and Cs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (90) (1.1 g).

¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=9.1, 2H), 7.79 (d, J=8.9, 1H), 7.67(dd, J=1.2, 7.6, 1H), 7.48 (dd, J=1.1, 8.0, 1H), 7.18 (s, 3H), 6.89 (s,1H), 6.75 (d, J=8.9, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25,131.13, 130.13, 126.55, 125.42, 123.45, 122.50, 122.17, 120.49, 119.10,113.24.

MS (ESI) [M+H]⁺=339

Example 6 Compound (106) of the Table I

According to route (B), a mixture of 3-aminoquinoline (316 mg) and2-chloro-3nitropyridine (315 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) andCs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (106) (374.1 mg).

¹H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.06 (d, J=2.3, 1H), 8.65 (d,J=1.8, 1H), 8.60 (d, J=8.3, 1H), 8.56 (d, J=4.5, 1H), 7.97 (dd, J=8.2,14.4, 2H), 7.69 (t, J=6.9, 1H), 7.59 (t, J=7.4, 1H), 7.08 (dd, J=4.6,8.3, 1H).

MS (ESI) [M+H]⁺=267

Example 7 Compound (112) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (958 mg) andaminopyrazine (522 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) and Cs₂CO₃(4.6 g) in 20 mL of t-BuOH gave compound (112) (728 mg).

¹H NMR (300 MHz, DMSO) δ 10.58 (s, 1H), 10.26 (s, 1H), 8.36 (s, 1H),8.27 (s, 2H), 7.91-7.74 (m, 2H), 7.50 (d, J=8.8, 1H), 7.37 (t, J=7.6,1H).

¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48, 142.18, 138.20, 137.55,135.74, 129.71, 126.99, 125.35, 123.84, 114.75.

MS (ESI) [M+H]⁺=255

Example 7 Compound (136) of the Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg) and2-amino-4methylpyridine (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (136) (35.4 mg).

¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.20(d, J=5.1, 1H), 7.94 (d, J=8.1, 1H), 7.84 (d, J=8.2, 1H), 7.64 (t,J=7.6, 1H), 7.49 (t, J=8.1, 1H), 6.83 (d, J=5.0, 1H), 2.43 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55, 147.40, 140.93,139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70, 113.75, 21.87.

MS (ESI) [M+H]⁺=237

Example 8 Method for Synthesizing the Compounds of the Present Invention

Typical Procedure for Pd-Catalysed Aminations

To a solution of halogeno compound (0.5 mmol, 1 equiv) in tert-butanol(2 mL) were added the amino moiety (0.55 mmol, 1.1 equiv), Cs₂CO₃ (456mg, 1.4 mmol, 2.8 equiv), Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) (5.8 mg, 0.01 mmol, 2mol %), Pd(OAc)₂ (2.2 mg, 0.01 mmol, 2 mol %). The reaction mixture washeated at 90° C. and stirred for 20 h under argon. The reaction mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel to yield pure compounds.

For example this procedure permitted to synthetize the followingcompounds:

Isoquinolin-5-yl-(3-methoxy-pyridin-2-yl)-amine

¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 8.66 (dd, J=1.7, 6.8, 1H), 8.55(d, J=6.0, 1H), 7.85 (d, J=5.0, 1H), 7.76 (d, J=6.0, 111), 7.69-7.58 (m,2H), 7.53 (s, 1H), 7.06 (d, J=7.7, 1H), 6.78 (dd, J=5.1, 7.8, 1H), 3.99(s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 153.23, 146.60, 142.97, 142.79, 138.53,134.82, 129.53, 129.13, 127.95, 121.66, 119.82, 115.18, 115.05, 114.09,100.15, 55.80.

(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine:(6) of the tableI

¹H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.17 (d, J=5.1, 1H), 8.09 (s,1H), 7.98 (d, J=8.9, 1H), 7.76 (dd, J=1.2, 7.6, 1H), 7.61 (dd, J=1.0,8.0, 1H), 7.26 (t, J=7.8, 2H), 7.15 (d, J=8.7, 1H), 6.83 (d, J=5.0, 1H),2.46 (s, 3H).

¹³C NMR (75 MHz, CDCl3) δ 153.52, 153.14, 149.90, 147.43, 143.68,138.08, 131.37, 129.98, 126.56, 125.58, 123.58, 119.17, 114.52, 114.02,21.84.

(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine:(10) of the table I

¹H NMR (300 MHz, DMSO) δ 9.17 (d, J=2.5, 1H), 8.97 (d, J=2.4, 1H), 8.79(s, 1H), 7.94-7.79 (m, 3H), 7.58-7.46 (m, 2H), 7.31 (d, J=7.9, 1H), 6.88(dd, J=5.0, 7.9, 1H), 3.94 (s, 3H).

Pharmacological Data

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treating AIDS.

Example 9 Development of IDC16 Derivative Compounds

The inventors have shown that compound IDC16 (BAKKOUR et al., citedabove, 2007) interacts functionally with the SF2/ASF complex and thuscontributes to blocking alternative splicing during HIV replication,leading to the termination of the production of Tat protein.

Accordingly, the family of polycyclic indoles, to which compound IDC16belongs, is known to exhibit the properties of DNA intercalating agents.Such compounds thus present a risk in terms of undesirable side effects.

The inventors thus sought to develop novel molecules exhibiting activitycomparable to IDC16, in terms of activity inhibiting HIV splicing, butwhile not exhibiting the characteristics of DNA intercalating agents.

In their initial hypothesis, the inventors considered that the two polarheterocycles at the two ends of compound IDC16 were associated with itsactivity and that the two median rings were of less importance.

Based on this hypothesis, the inventors considered that:

-   -   the nitrogen of the indoline and of the D ring of IDC16 might        act as acceptors of hydrogen bonds;    -   the N-methylated 4-pyridinone motif might be preserved in the        analogues;    -   the flat tetracyclic geometry was not optimal and it might be        wise to replace the B and C rings by other motifs to limit DNA        intercalating properties.

Example 10 Inhibition of HIV-1 Production in Infected Peripheral BloodMononuclear Cells (PBMCs)

Material and Methods

The first determination is that of the concentration of compound thatexhibits the fewest side effects in terms of cell viability andprogression of the cell cycle.

Within this framework, the peripheral blood mononuclear cells (PBMCs) ofhealthy donors are isolated by centrifugation on a FICOLL gradient. Thecells are then cultivated to a density of 2.5×10⁶ cells/ml with RPMImedium supplemented with 1% inactivated human AB serum, then incubatedat 37° C., 5% CO₂ for an additional hour. The peripheral bloodmononuclear cells are then recovered and cultivated for two days in RPMImedium supplemented with 10% fetal calf serum.

A standard experiment using 96 plates to test 30 molecules intriplicates including positive and negative controls, is performed asfollows:

50 10⁶ Ficoll purified PBMCs (10% DMSO 90% FCS) are washed with RPMI 10%FCS and resuspended in 25 ml of RPMI 10% FCS, glutamax containing 1000U/ml of IL2 and 5 μg/ml PHA. The cells are then incubated for 3 days at37° C. before to be washed with 50 ml PBS then with 50 ml RPMI 10% FCS.The cells are resuspended in 100 μl of RPMI 10% FCS containing 100 U/mlIL2 and seeded in 96 wells (1.5 10⁵ cells/well). Viral infection isperformed with 1 ng of AdaM/well. 100 μl of tested molecules atconcentration of 10 μM are added to each well. Virus production isdetermined by p24 antigen immunosorbent assays after 3 and 6 days ofinfection (Kit Innogenetics). Typically PBMCs are prepared from severalhealthy donors (around 11 different donors). Dose response curves werethen established with selected compounds to determine IC₅₀.

Protocol for Cytotoxicity:

To evaluate the cytoxicity of different compounds we used the sameprotocol as above to seed the HOS-CD4⁺-CCR5⁺ cells or PBMCs in a finalvolume of 100 μl without adding the virus. After an incubation for 48 hat 37° C., the medium was removed and cells were incubated with 20 μl ofCellTiter96 AqueousOne solution to determine the number of viable cellsin proliferation and cytotoxicity assays (Promega). CellTiter96AqueousOne is a colorimetric assay solution that has many advantagescompared to MTT assays and gives us satisfactory results.

We have also evaluated the effect of selected molecules on CD4 and CD8proliferation using the division tracking dye carboxyfluoresceindiacetate succinimidyl ester (CFSE) (In vitrogen).

RESULTS Inhibition of p24 production in HIV infected PBMCs from Compoundnumber IC₅₀ in nM  different donors Formula (Ia) 1 nd 4 out 6 donnors 60.1 9 out 14 donnors 33 nd 5 out 6 donnors 34 nd 6 out 8 donnors 35 nd 6out 8 donnors 36 nd 6 out 8 donnors 37 nd 4 out 6 donnors 38 nd 4 out 6donnors 42 nd 4 out 6 donnors 43 0.1 8 out of 10 donnors 44 nd 4 out 6donnors 45 nd 4 out of 4 donnors 46 nd 4 out of 4 donnors 48 nd 4 out 4donnors 50 nd 4 out of 4 donnors 64 nd 5 out of 5 donnors 68 nd 4 out of4 donnors 69 nd 4 out of 4 donnors 70 nd 4 out of 4 donnors 71 nd 4 outof 4 donnors 72 nd 4 out of 4 donnors 73 nd 4 out of 4 donnors 74 nd 4out of 4 donnors Formula (Ib) 75 nd 6 out of 7 donnors 77  0.05 11 outof 13 donnors 78 nd 7 out of 8 donnors 79 nd 7 out of 8 donnors 80 1   7out of 8 donnors 81 nd 4 out of 4 donnors 82 nd 4 out of 4 donnors 86 nd3 out of 4 donnors 87 nd 4 out of 4 donnors 88 nd 4 out of 4 donnors 900.1 8 out of 10 donnors 92 nd 3 out of 5 donnors 96 nd 5 out of 6donnors 104 nd 4 out of 4 donnors Formula (Ic) 106 0.5 6 out of 6donnors Formula (Ie) 109 nd 8 out of 8 donnors 112 0.1 12 out of 13donnors Formula (Io) 136 nd 6 out of 8 donnors 139 nd 4 out of 4 donnors140 nd 4 out of 4 donnors 141 nd 4 out of 4 donnors

Example 11 Inhibition of HIV-1 Production in Infected Macrophages

In order to generalize the HIV-1 replication effect of the molecules ofthe present invention to other cell types, we examined various steps ofthe viral cycle in cells treated with the various drug at aconcentration of 5 μM and submitted to one-round infection.

For such experiences, macrophages can be infected by the Ada-M R5 HIVstrain and treated for 18 hours with various concentrations of thecompounds of the present invention. The culture medium is theneliminated and the cells washed with an abundance of PBS. The cells arethen cultivated under normal conditions. The culture medium and thecells are then collected at days 4, 7 and 14. Finally, virus replicationis measured indirectly by determining the level of p24 antigen in boththe culture supernatant and the cellular lysate by the ELISA method. Inparallel, cell viability of the macrophages in the presence of thecompounds of of the present invention is measured as before.

For this purpose, we exposed HOS-CD4⁺-CCR5⁺ cells to defective virionsobtained by cotransfecting 293T cells with a plasmid encoding the R5envelope of the AD8 strain and another plasmid containing the entireHIV-1 genome mutated in the envelope gene and harbouring a luciferasemarker gene fused to nef (Connor R I, Chen B K, Choe S, Landau N R.(1995) Vpr is required for efficient replication of humanimmunodeficiency virus type-1 in mononuclear phagocytes. Virology 206:935-944.). The amounts of luciferase activity in cells infected withthese virions reflect both the number of integrated proviruses andexpression of multiply spliced species encoding nef/luc. Two dayspost-infection, luciferase activity in HOS-CD4+-CCR5+ infected cells wasmeasured.

The results are shown below:

Compound Results

+

−

+

−

+

−

−

−

−

+

−

The results established that the compounds of the present invention showa luciferase inhibitory effect, thus showing that these compoundsinhibit viral RNA splicing.

A further object of the invention consists of a pharmaceuticalcomposition comprising at least one compound of formula (Ib) or (Ie) oranyone of compounds (8), (75), (77)-(84), (86)-(104), (109)-(117),(155)-(158) and their pharmaceutically acceptable salts, such ashydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate and, optionally, a pharmaceutically acceptable support.

As examples of pharmaceutically acceptable supports, the composition caninclude emulsions, microemulsions, oil in water emulsions, anhydrouslipids and water in oil emulsions or other types of emulsions.

The inventive composition can further include one or more additives suchas diluents, excipients, stabilizers and preservatives. Such additivesare well known to those skilled in the art and are described notably in“Ullmann's Encyclopedia of Industrial Chemistry, 6^(th) Ed.” (variouseditors, 1989-1998, Marcel Dekker) and in “Pharmaceutical Dosage Formsand Drug Delivery Systems” (ANSEL et al., 1994, WILLIAMS & WILKENS).

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

In this context they can be present in any pharmaceutical form which issuitable for enteral or parenteral administration, in association withappropriate excipients, for example in the form of plain or coatedtablets, hard gelatine, soft shell capsules and other capsules,suppositories, or drinkable, such as suspensions, syrups, or injectablesolutions or suspensions, in doses which enable the daily administrationof from 0.1 to 1000 mg of active substance.

Still a further object consists of the use of at least one compound offormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Tee) as defined above, andcompounds (1) to (168) as defined above, or one of its pharmaceuticallyacceptable salts according to the present invention in preparing a drugto treat, in a subject, a disease resulting from at least one splicinganomaly.

Therefore, the present invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),(Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above, and compounds(1) to (168) as defined above, or one of its pharmaceutically acceptablesalts according to the present invention for preparing a drug to treat,in a subject, a disease resulting from at least one splicing anomaly.

As used in the present application, the term “subject” refers to amammal such as a rodent, cat, dog, primate or human, preferably saidsubject is a human.

Preferably, the inventive compounds have the ability to inhibitpre-messenger RNA splicing processes that are either constitutive or,more specifically, dependent on regulating sequences known as an ESE(exonic splicing enhancer), ISE (intronic splicing enhancer), ESS(exonic splicing silencer) and ISS (intronic splicing silencer).

In a particularly preferred way, splicing processes are eitherconstitutive and/or or dependent on ESE regulating sequences.

Preferably, the present invention relates to the use of the at least onecompound of formula (I), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ti), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Tee) asdefined above, or one of its pharmaceutically acceptable salts accordingto the present invention, and more particularly of formula (Ia), (Ib),(Ic), (Ie) and (Io) as described above for preparing a drug to treat, ina subject, AIDS.

Therefore, the present invention relates to a one of said compounds, andmore particularly to a compound (1) to (168) or one of its acceptablesalts for treating AIDS.

Another object of the invention relates to a therapeutic method fortreating a subject for a genetic disease resulting from splicinganomalies comprising the administration of a therapeutically effectivequantity of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir)or (Iee) as defined above, more particularly of formula (Ia), (Ib),(Ic), (Ie) and (Io) as described above, and even more particularly of atleast one compound (1) to (168) or one of its acceptable salts.

Preferably, said genetic disease resulting from splicing anomalies isAIDS.

A “therapeutically effective quantity” means a quantity that inducesinhibition of the splicing of the pre-mRNAs of interest. Those skilledin the art will be able to determine said therapeutically effectivequantity based on their general knowledge and on the methods describedin the examples.

The compounds can be administered by any mode of administration such as,for example, by intramuscular, intravenous or oral route, etc.

In one embodiment according to the invention, said composition furtherincludes an excipient making it possible to formulate the inventivecompounds in such a way that said composition is provided in solid orliquid form to be prepared and administered by intravenous route.

The inventive compounds preferably will be administered by intravenousroute at a concentration of 80-100 mg/m². The concentration will bechosen by those skilled in the art according to the organ or tissue tobe treated, the state of advancement of the disease and the targetingmode used.

1. A compound having the following formula or a pharmaceuticallyacceptable salt thereof:

where: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxy group, a —NO₂group, a phenoxy group, or a (C₁-C₄)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, R′ is a hydrogenatom, a halogen atom, a (C₁-C₃)alkyl group, or a (C₁-C₄)alkoxy group, R″is a hydrogen atom or a (C₁-C₄)alkyl group, n is 1, 2, or 3, and n′ is 1or
 2. 2. The compound of claim 1, wherein: R is a hydrogen atom or a(C₁-C₃)fluoroalkoxy group, and n is
 1. 3. The compound of claim 1,wherein: R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group, R′ is ahydrogen atom, a halogen atom, or a (C₁-C₃)alkyl group, and n is 1 or 2.4. The compound of claim 1, wherein the compound has the followingformula or a pharmaceutically acceptable salt thereof:

where: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxy group, a —NO₂group, a phenoxy group, or a (C₁-C₄)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, R′ is a hydrogenatom, a halogen atom, a (C₁-C₃)alkyl group, or a (C₁-C₄)alkoxy group,with the proviso that R′ is different from a methyl group at position 4of the quinoline group, R″ is a hydrogen atom or a (C₁-C₄)alkyl group, nis 1, 2, or 3, and n′ is 1or
 2. 5. The compound of claim 1, wherein thecompound has the following formula or a pharmaceutically acceptable saltthereof:

where: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxy group, a —NO₂group, a phenoxy group, or a (C₁-C₄)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, R″ is a hydrogenatom or a (C₁-C₄)alkyl group, n is 1, 2, or 3, and n′ is 1 or 2, withthe proviso that when n is 1, R is not a hydrogen atom, a methyl groupin para of the bond linked to NR″, an ethoxy group in para of the bondlinked to NR″, nor a fluorine atom in para of the bond linked to NR″. 6.A compound selected from the group consisting of: (8)Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine, (75)4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine, (77)8-chloro-N-(4-methoxyphenyl)quinolin-2-amine, (78)4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (79)N-(4-methoxyphenyl)-3-methylquinolin-2-amine, (80)3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (81)1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine, (82)N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine, (83)N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine, (84)N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine, (86)N-(3-fluorophenyl)quinolin-2-amine, (87)8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine, (88)8-chloro-N-(3-fluorophenyl)quinolin-2-amine, (89)2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride, (90)8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (91)3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine, (92)3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine, (93)3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine, (94)8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine, (95)3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride,(96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, (97)4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride,(98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (99)8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (100)8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (101)N-(4-butoxyphenyl)-8-chloroquinolin-2-amine, (102)N-(4-phenoxyphenyl)quinolin-2-amine, (103)8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, (104)8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine, (155)N-(4-butoxyphenyl)-3-methylquinolin-2-amine, (156)4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine, (157)8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine, (158)N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine, andtheir pharmaceutically acceptable salts.
 7. The compound of claim 6,wherein the pharmaceutically acceptable salts are selected fromhydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, triflate, maleate, mesylate, formate, acetate, andfumarate.
 8. A pharmaceutical composition comprising at least onecompound as defined in claim
 1. 9. A pharmaceutical compositioncomprising at least one compound as defined in claim
 2. 10. Apharmaceutical composition comprising at least one compound as definedin claim
 3. 11. A pharmaceutical composition comprising at least onecompound as defined in claim
 4. 12. A pharmaceutical compositioncomprising at least one compound as defined in claim
 5. 13. Apharmaceutical composition comprising at least one compound as definedin claim
 6. 14. A pharmaceutical composition comprising at least onecompound as defined in claim
 7. 15. The pharmaceutical compositionaccording to claim 8, further comprising a pharmaceutically acceptablesupport.
 16. The pharmaceutical composition according to claim 9,further comprising a pharmaceutically acceptable support.
 17. Thepharmaceutical composition according to claim 10, further comprising apharmaceutically acceptable support.
 18. The pharmaceutical compositionaccording to claim 11, further comprising a pharmaceutically acceptablesupport.
 19. The pharmaceutical composition according to claim 12,further comprising a pharmaceutically acceptable support.
 20. Thepharmaceutical composition according to claim 13, further comprising apharmaceutically acceptable support.
 21. The pharmaceutical compositionaccording to claim 14, further comprising a pharmaceutically acceptablesupport.